title: An antimicrobial peptidomimetic induces Mucorales cell death through mitochondria-mediated apoptosis.
abstract: The incidence of mucormycosis has dramatically increased in immunocompromised patients. Moreover, the array of cellular targets whose inhibition results in fungal cell death is rather limited. Mitochondria have been mechanistically identified as central regulators of detoxification and virulence in fungi. Our group has previously designed and developed a proteolytically-resistant peptidomimetic motif D(KLAKLAK)2 with pleiotropic action ranging from targeted (i.e., ligand-directed) activity against cancer and obesity to non-targeted activity against antibiotic resistant gram-negative rods. Here we evaluated whether this non-targeted peptidomimetic motif is active against Mucorales. We show that D(KLAKLAK)2 has marked fungicidal action, inhibits germination, and reduces hyphal viability. We have also observed cellular changes characteristic of apoptosis in D(KLAKLAK)2-treated Mucorales cells. Moreover, the fungicidal activity was directly correlated with vacuolar injury, mitochondrial swelling and mitochondrial membrane depolarization, intracellular reactive oxygen species accumulation (ROS), and increased caspase-like enzymatic activity. Finally, these apoptotic features were prevented by the addition of the ROS scavenger N-acetyl-cysteine indicating mechanistic pathway specificity. Together, these findings indicate that D(KLAKLAK)2 makes Mucorales exquisitely susceptible via mitochondrial injury-induced apoptosis. This prototype may serve as a candidate drug for the development of translational applications against mucormycosis and perhaps other fungal infections.
authors.affiliation: David H. Koch Center, Department of Genitourinary Medical Oncology, the University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America ; Department of Infectious Diseases, the University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: E Magda
authors.initials: EM
authors.lastname: Barbu
authors.forename: Fazal
authors.initials: F
authors.lastname: Shirazi
authors.forename: Danielle M
authors.initials: DM
authors.lastname: McGrath
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Albert
authors.forename: Richard L
authors.initials: RL
authors.lastname: Sidman
authors.forename: Renata
authors.initials: R
authors.lastname: Pasqualini
authors.forename: Wadih
authors.initials: W
authors.lastname: Arap
authors.forename: Dimitrios P
authors.initials: DP
authors.lastname: Kontoyiannis
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D020816:Amino Acid Motifs; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009090:Mucorales / Q000187:drug effects* / Q000302:isolation & purification / Q000378:metabolism; D009091:Mucormycosis / Q000382:microbiology; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D013172:Spores, Fungal / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; D057786:Peptidomimetics; D017382:Reactive Oxygen Species; D000111:Acetylcysteine